Intermediates for tricyclic amines

ABSTRACT

5-(AMINOPROPYLIDENE)-DIBENZO(A,D)CYCLOHEPTENES HAVING ANTI-DEPRESSANT ACTIVITY.

United States Patent Oflice 3,822,322 INTERMEDIATES FOR TRICYCLIC AMINESGerald Rey-Ballet and Hans Spiegelherg, Basel, Switzerland, assignors toHolfmann-La Roche Inc., Nutley,

No Drawing. Application Apr. 23, 1970, Ser. No. 31,397,

now Patent No. 3,736,351, which is a division of application Ser. No.620,241, Mar. 3, 1967, now Patent No. 3,527,806. Divided and thisapplication Feb. 9, 1973, Ser. No. 330,931

Int. Cl. C07c 25/18, 25/22 US. Cl. 260-649 R 2 Claims ABSTRACT OF THEDISCLOSURE -(Aminopropylidene)-dibenzo[a,d]cycloheptenes havinganti-depressant activity.

This is a division of application Ser. No. 31,397 filed Apr. 23, 1970,now Pat. No. 3,736,351, which in turn is a division of application Ser.No. 620,241, filed Mar. 3, 1967, now US. Pat. No. 3,527,806.

BRIEF SUMMARY OF THE INVENTION This invention relates to novelintermediates and to compounds characterized by the formula AR (no andpharmaceutically acceptable acid addition salts there- DETAILEDDESCRIPTION As used herein, the term alkyl is to be understood to mean astraight or branched chain lower alkyl group, preferably one having froml-4 carbon atoms, such as, methyl, ethyl, propyl and butyl.

The term alkylene is to be understood to mean lower alkylene having from1-5 carbon atoms.

The term alkylidene is to be understood to mean a lower alkylidene,preferably one having from 1-4 carbon atoms, such as, methylidene.

The term alkenyl is to be understood to mean a straight or branchedchain lower alkenyl group, preferably one having from 2-4 carbon atoms,such as, allyl.

The term aralkylidene is to be understood to mean a lower aralkylidenegroup having from 7-10 carbon atoms, such as, benzylidene.

The terms halogen and halo include chlorine, bromine, fluorine andiodine; chlorine and bromine being preferred.

R and R taken together with the attached nitrogen atom, represent a 5-6ring atom heterocyclic radical, for example, l-pyrrolidinyl,l-piperidyl, l-piperazinyl and 4- morpholinyl.

The term anion is to be understood to mean an anion of an organic acidor inorganic acid, such as, chloride, sulfate, acetate,p-toluene-sulfonate and the like.

Patented July 2, 1974 Examples of compounds of this inventioncorresponding to Formula I are:

5-(3-Dimethylamino-propylidene)-10-allyl-dibenzo [a,d] cycloheptene;

5-(3-Dimethylamino-propylidene)-10-methy1-dibenzo [a,d]cycloheptene;

5-(3-Methylamino-propylidene)-IO-methyl-dibenzo [a,d]cycloheptene; andthe like.

In accordance with this invention, compounds characterized by theformula wherein R R R and R are as previously described, can be preparedby dehydrating a compound selected from the group consisting ofcompounds of the formulas wherein R R R and R are as previouslydescribed, R is selected from the group consisting of alkylidene andaralkylidene, A is an anion selected from the group consisting oforganic and inorganic anions, and X is hydrogen when Y is hydroxyl, andY is hydrogen when X is hydroxyl.

Compounds of Formula II are exemplified by:

5-Hydroxy-5-(3 dimethylamino propyl)-lO-methyl-dibenzo[a,d]cycloheptene, and the like.

Compounds of Formula III are exemplified by:

N-benzylidene-N-[3-(5-hydroxy-l0-methyl dibenzo[a,d]

cycloheptene-S-yl)-propyl] N methyl-ammonium-ptoluenesulfonate, and thelike.

The dehydration of compounds of Formulas II and III is convenientlycarried out with an anhydrous or hydrous hydrohalic acid. A preferreddehydrating agent is an alcoholic hydrohalic acid. However, otherdehydrating agents, such as phosphorus oxychloride, p-toluenesulfonylchloride, sulfuric acid, zinc chloride or potassium bisulfate, forexample, in an inert organic solvent such as, chloroform or methylenechloride, are also useful. The dehydration can be accelerated by heatingthe reaction mixture. The alkylidene and aralkylidene substituentspresent in the compounds of Formula III are saponified under theconditions given for the dehydration.

Another embodiment for the preparation of compounds of Formula Icomprises reacting a compound of the formula wherein R and R are aspreviously described, and B is selected from the group consisting ofvinyl and haloethyl,

with a compound of the formula wherein R and R are as previouslydescribed.

Compounds of Formula IV are exemplified by:

Examples of amines covered by Formula V are: methylamine, dimethylamine,ethylamine, diethylamine, and the like. Examples of heterocycliccompounds covered by Formula V are: pyrrolidine, piperidine, piperazine,morpholine and the like. The preferred compounds of Formula V are themonoand di-substituted amines.

The compounds of Formula IV, wherein B represented haloethyl, can beaminated by simple reaction with a compound of Formula V.

The compounds of Formula IV wherein B denotes vinyl can be aminated byaddition of the appropriate monoor di-substituted amine of Formula V.

The reaction of the haloethyl compounds of Formula IV with compounds ofFormula V can be conveniently carried out in the presence of inertorganic solvents, such as, benzene, toluene or the like. The reaction isconducted conveniently at elevated temperatures in the range of 50 to150 C., preferably of the boiling temperature of the reaction mixture.Readily volatile amines are expediently brought to reaction in a closedsystem at a temperature of about 100 C. Advantageously, the reaction ofthe two components is conducted in the presence of an acid-bindingagent, such as, anhydrous potassium carbonate. It is especiallyconvenient to utilize as the acid-binding agent a compound of Formula V.Under the latter condition, it is sufiicient to employ an excess of theamine of Formula V in the reaction with a compound of Formula IV.

The addition of amines of Formula V to the vinyl compounds of Formula IVis conveniently carried out in the presence of a metal, such as, lithiumor sodium; a metal amide, such as, sodium or potassium amide; or ametalorganic compound, such as, a Grignard compound, preferably at atemperature in the range of 50 to 150 C.

The compounds of Formula I, wherein R and R are alkyl, obtained bydehydration of compounds of Formulas II and III or by amination ofcompounds of Formula IV, can be dealkylated in a manner similar to thosepreviously utilized for compounds having a secondary amino group. Thus,the dealkylation can, for example, be carried out by allowing a cyanogenhalide, such as, cyanogen bromide or a haloformate, preferably ethylchloroformate to act on the dialkylamino group of a compound of FormulaI. In this reaction, one of the two alkyl groups on the nitrogen atom isexchanged for the cyano or alkoxycarbonyl residue and then, in turn, isitself replaced by hydrogen by saponification.

The compounds of Formula I can be converted into acid addition saltswith organic or inorganic acids. Thus, they 4 form pharmaceuticallyacceptable acid addition salts with organic acids, such as, acetic acid,oxalic acid, citric acid, lactic acid, and the like, as well as withinorganic acids, such as, hydrochloric acid, hydrobromic acid, sulfuricacid, and the like.

The tricyclic amines obtained in accordance with the invention consistof an isomer mixture, caused by cistrans-isomerism and, insofar as theyare substituted in the aromatic rings, by position isomerism. Separationof the isomers can be accomplished utilizing methods such as fractionalcrystallization based on the difiYerent solubilities of the bases oracid addition salts. It is advantageous with ring-substituted compoundsto separate the isomeric starting compounds prior to further processing.

The compounds of Formula I and the pharmaceutically acceptable acidaddition salts thereof obtained in accordance with the invention exhibitmultiple actions on the nervous system. The compounds are useful asantidepressants. They are useful in that they reverse either endogenousor exogenous depression of the central nervous system. Preferred for itsantidepressive action is S-(dimethylamino-propylidene-10-allyl-dibenzo[a,d] cycloheptene.

The compounds of Formula I and their pharmaceutically acceptable acidaddition salts can be administered orally or parenterally with dosageadjusted to individual requirements. They can be administeredtherapeutically, for example, orally or parenterally, by incorporating atherapeutic dosage in a conventional dosage form, such as tablets,capsules, elixirs, suspensions, solutions or the like. They can beadministered in mixture with conventional pharmaceutical carriers orexcipients, such as, for example, corn starch, calcium stearatemagnesium carbonate, calcium silicate, dicalcium phosphate, talc,lactose, and the like. Moreover, they can be administered in thepresence of buffers, or agents used to adjust to isotinicity, and thepharmaceutical dosage forms can, if desired, be subjected toconventional pharmaceutical expedients such as, for example,sterilization. As stated above, the dosage can be adjusted to individualrequirements. They can also contain other therapeutically valuablesubstances.

The quantity of active medicament which is present in any of theabove-described dosage forms is variable. It is preferred, however, toprovide capsules or tablets containing from about 5 mg. to about 50 mg.of the Formula I base or an equivalent amount of a medicinallyacceptable acid addition salt thereof. For parenteral administration, itis preferred to provide a solution containing from about 10 mg./ml. toabout 20 mg./ml. of the Formula I base, or an equivalent quantity of asalt thereof.

The frequency with which any such dosage form will be administered to apatient will vary, depending upon the quantity of active medicamentpresent therein and the needs and requirements of the patient, asdiagnosed by the prescribing physician. Under ordinary circumstances,however, up to about 3 mg./kg. of the compound can be administeredorally daily in several dosages. It is to be understood, however, thatthe dosages set forth therein are exemplary only and that they do not,to any extent, limit the scope or practice of this invention.

The compounds of Formulas II, HI and IV are new and are usefulintermediates for the preparation of compounds of Formula I.

Compounds of Formula II, in which X represents hydroxyl and Y representshydrogen can be prepared from a 10- to 11halo-dibenzo[a,d]cycl0hepten-5-one, as follows:

A ketal of 10-bromo-dibenzo[a,d]cycloheptene-5-one is reacted utilizinga metal-organic reaction with an alkyl, alkenyl or benzyl halide toyield the corresponding 10- alkyl, alkenyl or benzyl derivative which,by splitting off the protecting group, can be converted into the10-alkyl, alkenyl or benzyl-dibenzo[a,d]cyclohepten-5-one, a keyintermediate for the starting compounds represented by Formulas HI andIV.

The ketone can be linked utilizing a metal-organic reaction to anN-monoor N-disubstituted 3-amino-propyl halide and transformed byhydrolysis into the desired 5- hydroxy-S-(N-monoor N-disubstituted3-aminopropyl) derivative.

It is also possible to react the ketone under the same conditions withan N-monoor N-disubstituted 3-aminopropyne-( 1) and to hydrogenate thetriple bond of the .S-hydroxy-S-(N-monoor N-disubstituted 3amino-propyne-( l) derivative obtained after hydrolysis to the singlebond propane. Both processes lead to a S-(N-monoor N- disubstituted3-aminopropyl)-10-alkyl, alkenyl or benzyldibenzo[a,d]cycloheptene ofFormula II.

Another process for preparing the compounds of Formula II comprisesreacting a -alkyl, alkenyl or benzyldibenzo[a,d]cyclohepten-S-one withan N-mono or N- disubstituted 3-aminopropyl halide in the presence of 2gram atoms of sodium per mole of ketone and hydrolyzing the reactionmixture.

The starting compounds of Formula II werein X represents hydrogen and Yrepresents hydroxyl can also be synthesized as follows:

The ketone named above is reacted utilizing a metalorganic reaction'with an ethyl halide and is thereafter hydrolyzed. The carbinol formedis converted by dehydration into the corresponding ethylidene compoundhaving a semicyclic double bond. The ethylidene group is subsequentlytransformed into the acetyl group by the action of oxidation agents andtreatment of the oxidation product with aqueous mineral acid. TheS-acetyl derivative obtained is thereupon reacted with a monoordi-substituted amine in the presence of formaldehyde to give thecorresponding S-amino-ethylcarbonyl compound and reduced to the desiredcarbinol of Formula H.

The starting materials of Formula III can be prepared by reacting, forexample, the above-mentioned IO-alkyl, alkenyl orbenzyl-dibenzo[a,d]cyclohepten-S-one, as previously described, in thepresence of 2 gram atoms of sodium per mole of ketone with al-substituted 3-amino propyl halide, and hydrolyzing the reactionproduct to the corresponding S-hydroxy-S-amino propyl derivative. Thisis reacted with an aliphatic or araliphatic aldehyde, preferably withacetaldehyde or benzaldehyde and the resulting Schiffs base isquaternized through the action of an alkylating substance, particularly,through the treatment with an alkyl halide or an alkyltoluene sulfonate.

The starting compounds of Formula 1V in which B represents a haloethylgroup can be prepared from a 10- or 1l-halodibenzo[a,d]cyclohepten-S-oneas follows:

10 Bromo-dibenzo[a,d]cyclohepten-S-one is reacted utilizing ametal-organic reaction with a propyl halide exhibiting an ether functionsuch as, 3-methoxypropyl bromide and is thereafter converted byhydrolysis into the corresponding tertiary carbinol.

It is also possible to react the ketone under the same conditions with apropyne-(l) exhibiting an ether function, such as, 3-methoxy-propyne-(1)and to hydrogenate up to the single bond the triple bond of theS-hydroxy- S-methoxy-propyne derivative obtained by hydrolysis.

The bromine atom of the S-hydroxy-5-methoxy-propyl- IO-bromo-dibenzo[a,d]cycloheptene obtained can, after dehydration of the carbinol hasbeen effected, be replaced by the alkyl, alkenyl or benzyl residue byreaction with an alkyl, alkenyl or benzyl halide utilizing ametal-organic reaction.

The ether function of the S-methoxy-propylidene compound thus obtainedis replaced by bromine or chlorine by treatment with a hydrohalic acid,such as, an aqueous, concentrated solution of hydrobromic acid or asolution of hydrogen bromide in glacial acetic, or also by treatmentwith phosphorus oxychloride, or, preferably, by treatment with borontrifluoride in chloroform.

The 5-(halo-propylidene)-10-alkyl, alkenyl orbenzyldibenzo[a,d]cycloheptene obtained in this manner is a startingcompound of the present process corresponding to Formula IV, wherein Bis haloethyl.

The same compound is also accessible from the 10- alkyl, alkenyl orbenzyl-dibenzo[a,d]cyclohepten-S-one. For example, the ketone isreacted, as previously described, utilizing a metal-organic reactioneither with a propyl halide exhibiting an ether function, such as,3-methoxy-propyl bromide or with a corresponding propyne-( 1)derivative, such as, 3-methoxy-propyne-(1). The5-hydroxy-S-methoxy-propyl-10-alkyl, alkenyl or benzyldibenzo[a,d]cycloheptene formed after hydrolysis has taken place can beconverted as previously described into the desired S-halo-propylidenecompound of Formula IV.

A further route to the compound of Formula IV, wherein B is haloethyl,likewise begins with the 10-alkyl, alkenyl orbenzyl-dibenzo[a,d]cyclohepten-S-one.

The ketone is reacted utilizing metal-organic reaction with acyclopropyl halide. The 5-hydroxy-5-cyclopropy1 derivative obtained byhydrolysis can be converted into the desired 5-bromopropy'lidenecompound of Formula IV by the action of a concentrated hydrohalic acid,such as, hydrobromic acid.

Starting compounds of Formula IV in which B represents the vinyl groupcan likewise be manufactured from the 10-alkyl, alkenyl orbenzyl-dibenzo [a,d]cyclohepten- 5-one.

The ketone is reacted, for example, with the help of a metal-organicreaction, with a l-propenyl halide, such as, l-propenyl bromide. The5-hydroxy-5-propen-(1)-yl derivative formed can be converted into thecorresponding 5-propenylidene compound of Formula IV by the action ofdehydrating agents.

The compounds of Formula IV, wherein B represents the vinyl group can betransformed by addition of hydrogen halide into compounds of Formula IIIin which B denotes the haloethyl group.

The following examples are presented to further illusstrate theinvention. All temperatures are in degrees Centigrade, unless otherwisementioned.

EXAMPLE 1 15.8 g. of 5-(3-chloro-propylidene)-10-allyl-dibenzo[a,d]cycloheptene, 75 ml. of dry toluene and 50 ml. of dimethylamine areheated at for 20 hours in a pressure vessel. After expelling the excessdimethylamine, the reaction mixture is diluted with ether. Theetherealsolution is washed with water and subsequently extracted withdilute hydrochloric acid. The aqueous acidic extract is made alkalinewith potassium carbonate. The 5-(3-dimethylamino-propylidene) 10allyldibenzo[a,d]cycloheptene which separates as an oil is taken up inether. After the ether is removed by evaporation, the product is removedby distillation and has a b.p. of 155/ 0.01 mm. of mercury.

The 5 (3 chloro propyli-dene)-10-allyl-dibenzo[a,d] cyclohepteneemployed above as starting material can be prepared as follows:

15 g. of magnesium shavings are overlaid with 50 ml. of dry ether andtreated with 0.5 ml. of methyl iodide. After the vigorous initialreaction has subsided somewhat, a solution of 54.6 g. of1-chloro-3-methoxy-propane in 300 ml. of dry ether is added dropwise andthe temperature of the reaction mixture is maintained at its boiling.The mixture is subsequently heated at 45 under reflux conditions for aperiod of 3 hours, cooled with ice-water,

' treated dropwise over a 1 hour period with a solution of 69.2 g. of10-bromo-di-benzo [a,d]cyclohepten-S-one in 500 ml. of dry ether andagain heated at 45 under reflux conditions for 16 hours. The reactionmixture is again cooled with ice-water and treated with a cold,saturated solution of ammonium chloride. The organic layer is removedand the aqueous phase is shaken out with two ml. portions of ether. Thecombined ether extracts were dried over sodium sulfate and evaporated.The residual 5-hydroxy 5 (3-methoxy-propyl) l brorno-dibenzo[a,d]cycloheptene, after recrystallization from petroleum ether, melts at82-84".

50 g. of -hydroxy-5-(3-methoxy-propyl)-10-bromodibenzo[a,d]cyclohepteneand 500 ml. of a 3 percent alcoholic hydrochloric acid solution areheated on a steambath under reflux conditions for a period of 3 hours.After the alcohol is driven off, the residue is taken up in ether. Theethereal solution is successively washed with water, bicarbonatesolution, and water, dried over sodium sulfate and evaporated. Theresidual 5-(3-methoxy-propylidene)- -bromo-dibenzo[a,d]cycloheptene,after recrystallization from petroleum ether, boils at 155 /0.05 mm. ofmercury and melts at 113-115".

2 g. of magnesium shavings are treated with a few drops of methyliodide. As soon as the reaction commences, a solution of 22.7 g. of5-(3-methoxy-propylidene)-l0-bromo-dibenzo[a,d]cycloheptene in 100 ml.of dry, peroxide-free tetrahydrofuran is added dropwise and the internaltemperature is maintained at 50 to 55. The reaction mixture issubsequently boiled under reflux conditions for an additional 3 hours,whereby substantially all of the magnesium is consumed.

The resulting light-brown solution is cooled to 10- treated with asolution of 7.65 g. of allyl bromide in 25 ml. of dry peroxide-freetetrahydrofuran, stirred under reflux conditions for a period of 90minutes, cooled with ice-water, and treated with a cold saturatedaqueous ammonium chloride solution. The tetrahydrofuran is subsequentlyevaporated under reduced pressure, and the residue is taken up in ether.The ethereal solution is washed with water, dried and evaporated. Theresidual 5 (3 methoxy-propylidene)-10-allyl-dibenzo[a,d]cyclohepteneboils at 160/0.06 mm. of mercury.

16 g. of 5-(3-methoxy-propylidene)-10-allyl-dibenzo [a,d]cyclohepteneare dissolved in 100 ml. of dry chloroform, cooled to 10 and treateddropwise with a solu tion of 6.5 g. of boron trichloride in 30 ml. ofchloroform. After standing at room temperature for a period of 16 hours,the reaction mixture is successively washed with water, a sodiumbicarbonate solution and water, dried and evaporated. The residual5-(3-chloropropylidene)-10- allyl-dibenzo[a,d]cycloheptene boils at145l50/0.0l mm. of mercury.

EXAMPLE 2 18 g. of 5-hydroxy-5-(3-dimethylamino-propyl)-10-methyl-dibenzo[a,d]cycloheptene and 180 ml. of 3 percent alcoholichydrochloric acid are heated on a steam-bath under reflux conditions fora period of 2 hours and subsequently evaporated to dryness. The residual5-(3-dimethylamino propylidene) 10 methyl-dibenzo [a,d]cyclohepteneboils at 165-170/0.03 mm. of pressure.

The 5-hydroxy-5-(3dimethylamino-propyl)-10-methyl-dibenzo[a,d]cycloheptene employed aboveas starting material can be prepared as follows:

50 g. of IO-bromo-dibenzo[a,d]cyclohepten-5-one in 150 ml. of ethyleneglycol are saturated with hydrochloric acid gas with vigorous stirring.The temperature of the reaction mixture rises to 85 The temperature ofthe reaction mixture is subsequently maintained at 100 on a steam-bathfor a period of 1 hour, then cooled and poured into excess ice-coldcaustic soda; The precipitated 5,5-ethylenedioxy-10-bromo dibenzo [a,d]cycloheptene, after recrystallization from petroleum ether, melts at171-172".

9 g. of magnesium shavings are treated with a few drops of methyliodide. As soon as reaction takes place, a solution of 78.6 g. of5,5-ethylenedioxy-10-bromo-dibenzo[a,d]cycloheptene in 450 ml. of dry,peroxide-free tetrahydrofuran is added dropwise and the internaltemperature maintained between 40 and 42. The reaction mixture issubsequently heated under reflux conditions for an additional 3 hours,whereby substantially all of the magnesium is consumed.

The resulting light-brown solution is cooled with icewater, treated witha solution of 34 g. of methyl iodide in 50 ml. of dry, peroxide-freetetrahydrofuran, stirred under reflux conditions for a period of 2hours, again cooled with ice-water and treated with a cold saturatedammonium chloride solution. The tetrahydrofuran is evaporated underreduced pressure and the residue is taken up in chloroform. Thechloroform solution is Washed with water and evaporated. The residual5,5- ethylenedioxy-lO-methyl dibenzo[a,d]cycloheptene may berecrystallized from methanol.

25 g. of 5,5-ethylenedioxy-IO-methyl-dibenzo[a,d]cycloheptene, 25 ml. ofconcentrated hydrochloric acid and 250 ml. of acetone are heated underreflux conditions on the steam-bath for a period of 1 hour. The solventis subsequently removed by evaporation. The residue is taken up inmethylene chloride, washed with a sodium bicarbonate solution and water,and evaporated. The residual IO-methyl-dibenzo[a,d]cyclohepen-5-one maybe recrystallized from methanol.

8 g. of Gilman alloy are overlaid with 20 ml. of dry ether and treatedwith 0.5 m1. of methyl iodide. After the vigorous initial reaction hassubsided, 30 g. of l-chloro- 3-dimethylamino-propane in ml. of dry etherare added dropwise and the temperautre of the reaction mixture ismaintained at its boiling. The mixture is heated at 45 under refluxconditions for an additional period of 4 hours, then cooled withice-water, and treated dropwise over a period of 1 hour with a solutionof 20 g. of IO-methyl-dibenzo[a,d]cyclohepten-5-one in ml. of ether. Thereaction mixture is subsequently stirred at 40 under reflux conditionsfor a period of 6 hours, then cooled with ice-water and treated with acold, saturated ammonium chloride solution. The organic layer isseparated. The aqueous phase is shaken out twice with 100 ml. portionsof ether. The ether extracts are combined, dried over sodium sulfate andevaporated. The residual 5 -hydroxy-5- 3-dimethylamino-pro pyl-10-methyl-dibenzo[a,d]cycloheptene can be processed as previously setout without further purification.

EXAMPLE 3 A Grignard compound prepared from 13.2 g. of bromobenzene, 2g. of magnesium and 50 ml. of absolute ether is treated with 13.9 g. of5-propenylidene-IO-methyl-dibenzo[a,d]cycloheptene. The mixture ischarged into a moisture-free autoclave. The ether is removed byevaporation with slight heating. The reaction mixture is cooled, chargedwith 50 ml. of anhydrous methylamine, and heated at 80 for a period of10 hours. The reaction mixture is thereafter cooled and taken up inether. The excess methylamine is removed by distillation. The dispersedmagnesium hydroxide is precipitated with 25 ml. of water. Thesupernatant ether solution is removed by decantation and the residue isshaken out twice with ether. In order to remove the last of theremaining methylamine, the combined ether fractions are concentratedunder reduced pressure and subsequently dried over sodium sulfate. Theditficulty soluble5-(3-methylaminopropylidene)-10-methyl-dibenzo[a,d]cycloheptene acetatewhich is precipitated from an ethereal solution by addition of 3 g. ofglacial acetic is treated with dilute ammonia. The free base whichseparates is extracted with ether. The resulting ethereal solution isdried and treated with ethanolic hydrochloric acid. The5-(3-methylaminopropylidene) -10-methyl-dibenzo [a,d] cycloheptenehydrochloride which is formed after recrystallization from ethanol/ethylether melts at 200-202".

The S-propenylidene-IO-methyl dibenzo[a,d]cycloheptene employed as thestarting material can be prepared as follows:

6.45 g. of magnesium shavings are treated with 21.6 g. of allyl bromidein ml. of absolute ether to form an allyl magnesium bromide solution. Tothis are added dropwise 16.7 g. of IO-methyl-dibenzo[a,dJcyclohepten-S-one in 100 ml. of absolute ether and 50 ml. of absolute benzene over aperiod of 1 hour. The reaction mixture is subsequently heated underreflux conditions for a period of 1 hour and thereafter treated with asaturated ammonium chloride solution. The organic layer is separated.The aqueous phase is extracted with ether. The combined ether extractsare evaporated. The S-hydroxy-S-allyl-IO-methyl-dibenzo[a,d]cycloheptene(20 g.) which separates as a yellow oil is stirred and heated at 90 with10 g. of acetic acid anhydride and 10 ml. of absolute toluene. 0.5 m1.of acetyl chloride are introduced when the internal temperature reaches85. The internal temperature thereupon rises to 100. Thereafter, thereaction mixture is cooled, diluted with ether, washed with aqueousammonia and dried. The residual S-propenylidene 10-methyldibenzo[a,d]cycloheptene, after evaporation of the ether, is ayellow-brown oil.

EXAMPLE 4 11.8 g. of -(3-chloropropylidene)-10-methyl-dibenzo[a,d]cycloheptene, 50 ml. of toluene and 50 ml. of methylamine areheated at 120 for 20 hours in a pressure vessel. The excess methylamineis subsequently driven off under reduced pressure. Thereafter, thereaction mixture is diluted with ether, washed with water and extractedwith dilute hydrochloric acid. This aqueous acidic solution is madealkaline with potassium carbonate. The oil which separates is shaken outwith ether. The residual, oily 5(3-methylamino-propylidene)-l0-methyl-dibenzo [a,d]cycloheptene, afterevaporation of the solvent, boils at 160/ 0.01 mm. of mercury. Thehydrochloride addition salt thereof melts at 201-203 afterrecrystallization from ethanol/ether.

The 5 (3-chloro-propylidene)-l0-methyl-dibenzo[a,d] cyclohepteneemployed as the starting material can be prepared as follows:

4 g. of magnesium shavings are treated with a few drops of methyliodide. As soon as reaction commences, 45.5 g. of 5 (3methoxy-propylidene)--bromo-dibenzo[a,d] cycloheptene in 200 ml. of dry,peroxide-free tetrahydrofuran are added dropwise and the internaltemperature of the reaction mixture is maintained between 50 and 55. Thereaction mixture is subsequently heated under reflux conditions for anadditional 3 hours, whereby substantially all of the magnesium isconsumed.

The resulting brown solution is cooled to 10-15, treated with a solutionof 17.95 g. of methyl iodide in 50 ml. of dry, peroxide-freetetrahydrofuran, stirred under reflux conditions for 90 minutes, cooledwith ice-water and treated with a cold saturated aqueous ammoniumchloride solution. The tetrahydrofuran is removed by evaporation underreduced pressure and the residue is taken up in ether. The etherealsolution is washed with water, dried over sodium sulfate and evaporated.After recrystallization from alcohol, the residual5-(3-methoxypropylidene) 10-methyl-dibenzo[a,d]cycloheptene melts at125-428".

11 g. of 5-(3-methoxy-propylidene)-IO-methyl dibenzo [a,d]cyclohepteneare dissolved in 100 ml. of methylene chloride, cooled to --10 C., andtreated dropwise with a solution of 6 g. of boron trichloride in 30 ml.of methylene chloride. After standing at room temperature for 15 hours,the reaction mixture is washed with water, with a sodium bicarbonatesolution and again with water, dried and evaporated. The residual5-(3-chloro-propylidene)- 10 methyl-dibenzo[a,d]cycloheptene boils at155-158 and 0.03 mm. of mercury.

EXAMPLE 5 13.2 g. of crude N-benzylidene-N-[3-(5-hydroxy-10-methyl-dibenzo[a,d] cycloheptene5-yl)-propyl]-N-methyl-ammonium-p-toluenesulfonate are dissolved in 100ml. 1/N hydrochloric acid and warmed for 15 minutes on a water bath,cooled and alkalized by the addition of potassium carbonate. Theprecipitated oil is extracted with ether. The extract is dried andtreated with ethanolic hydrochloric acid. After recrystallization fromethanolether, the precipitated 5 (3-methylamino-propylidene)-IO-methyI-dibenzo[a,d]cycloheptene hydrochloride melts at 200-202.

The N-benzylidene-N-[S (5 hydroxy-lO-methyl-dibenzo[a,d]cycloheptene 5yl)-propyl]-N-methyl-ammonium-p-toluenesulfonate utilized as thestarting material can be prepared according to the following:

6.7 g. of 10-methyl-dibenzo[a,d]cyclohepten-S-one, prepared according tothe procedure of Example 2, are dissolved in 20 ml. of toluene and addeddropwise with agita tion to 30 ml. of liquid ammonia previously driedover sodium chips, 1.4 g. of sodium are added to the reaction mixturepiece by piece over a period of 30 minutes. The mixture is agitated foran additional hour and then reacted with 3.5 g. of freshly distilledl-chloro-3-amin0- propane (free base) in 20 ml. of toluene. The reactionmixture is carefully treated with water after 12 hours of agitation. Theorganic phase is separated and treated with 4 g. of benzaldehyde. Thetoluene and the liberated water are removed by distillation underreduced pressure. The residual benzylidene compound is mixed with 5.0 g.of the methyl-p-toluenesulfonate, slowly heated to and maintained at for30 minutes, whereby the desired N- benzylidenc N[3-(S-hydroxy-lO-metbyl-dibenzo[a,d] cycloheptene 5yl)-propyl]-N-methyl-ammonium-ptoluenesulfonate is formed.

EXAMPLE '6 25 g. of ethyl chloroformate in 80 ml. of dry benzene areslowly dropped into a solution of 20 g. of5-(3-dimethylaminopropylidene) IO-methyl-dibenzo[a,d]cycloheptene in 80m1. of dry benzene. The reaction mixture is heated under refluxconditions over a period of 20 hours, then cooled, washed with three 200ml. portions of 3-N hydrochloric acid and with water, dried andsubsequently evaporated. The residual oily 5(3-methyl-carbethoxyamino-propylidene) l0methyl-dibenzo[a,d]cycloheptene boils at 175 /0.01 mm. of mercury.

17.8 g. of 5-(3-methyl-carbethoxyamino-propylidene)-l0-methyl-dibenzo[a,d]cycloheptene, 20 g. of potassium hydroxide and 200ml. of n-butanol are heated under reflux conditions in a nitrogenatmosphere with stirring for a period of 17 hours. The butanol issubsequently removed by distillation under reduced pressure. The residueis taken up in 170 ml. of sulfuric acid, heated at 70 for a brief time,then washed with two 200 ml. portions of hexane and made alkaline withcaustic soda. The oil which separates is extracted with ether. Theethereal solution is washed with water, dried and evaporated. Theresidual oily 5 (3-methyl-propylidene)-10-methyl-dibenzo[a,d]cycloheptene boils at /0.01 mm. of pressure. After recrystallizationfrom ethanol/petroleum ether, the compound melts at 201-203".

The active substance is homogeneously mixed with the talcum andmannitol, sieved, again thoroughly mixed and filled into No. 4 gelatincapsules.

11 EXAMPLE 8 Drages are formulated as follows:

Mg. 5-(Methylamino-propylidene)-10-methyl-dibenzo- [a,d]cycloheptene 25Mannitol 100 Maize starch 20 Talcum 5 A 10 percent aqueous pasteprepared from the maize starch is homogeneously mixed with the mannitol,the talcum and the active substance, granulated and pressed to kernelswhich can be coated with a sugar layer in the usual manner.

From the foregoing description and examples, it will be apparent tothose skilled in the art that various modifications are possible withoutdeparting from the scope of the invention and, therefore, saiddescription and examples are not to be construed as limiting theinvention except as defined by the appended claims.

12 1 We claim: 1. A compound of the formula 7 References Cited UNITEDSTATES PATENTS 9/ 1966 Hotfsommer et al. 260646 R 3/1968 Engelhardt260649 R HOWARD T. MARS, Primary Examiner UNITED STATES PATENT OFFICE aQERTIFICATE OF CORRECTION .Patent No. 3,822,322 Dated I J121y2, 1974Inventor(s)- 2 Gerald Rey-Bellet and Hans Spiegelberg It is certifiedthat error appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column l, line 10, after "Ser. No. 330,931" insert --C1aims priority,application Switzerland, March 17, 1966,

No, sew/sa Signed and sealed this 21st day of January 1975.

(SEAL) Attest:

MCCOY M. GIBSON JR. c. MARSHALL DANN Attescing Officer] Commissioner ofPatents

